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Quality of reporting in randomized controlled trials conducted in China on the treatment of cancer pain Expert Rev. Anticancer Ther. 11(6), 871–877 (2011)
Liming Lu†1, Jingchun Zeng2 and Ying Chen3 Department of Oncology, First Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou 510405, China 2 Department of Dermatology, Second Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou 510405, China 3 Institute of Chinese Medical Science, University of Macau, Block 3, 2 F, Av Padre Tomas Pereira, Taipa, Macau, China † Author for correspondence: Tel.: +86 137 5177 9800 Fax: +86 203 659 1748
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Background: Research in China has been rapidly gaining momentum, but as yet there is no systematic evaluation of quality of reporting in randomized controlled trials (RCTs) on the treatment of cancer pain conducted in China. Therefore, an assessment in this field is an imperative issue. Methods: A PubMed search of reports published between 1994 and 2009 followed by an examination and critical appraisal of reporting in RCTs on the treatment of cancer pain was conducted in China. All reports had been examined to describe their general characteristics and evaluate the quality of their reporting. Quality of reporting was assessed against a subset of criteria adapted from the Consolidated Standards of Reporting Trials (CONSORT) statement. Results: A total of 46 RCTs were included in full text. The frequency of RCTs was found to increase over time: from one (2.2%) in 1994–1997 to 28 (60.9%) in 2006– 2009. There were fewer papers published in this field in foreign journals, as funding sources and opportunities for collaborative research with foreigners are still limited. Visual analogue scales were the main method of cancer pain evaluation (19 reports; 41.4%). Only 12 studies (26.1%) are deemed to have authentic randomization and 36 papers (78.3%) provided no information about blinding of either participants or investigators. In 22 papers (47.8%), there was no information about the length of time for which participants were followed. Only 15 (32.6%) of the included trials reported approval by an ethics committee and 17 (37.0%) adequately discussed informed consent. Conclusion: The quality of reporting in RCTs on the treatment of cancer pain conducted in China needs to be improved. Three critical steps should be strictly conducted including randomization, blinding and follow-up. Reporting of RCTs in this field conducted in China should meet and keep up with the standards of CONSORT statement. Keywords : cancer pain • quality assessment • randomized controlled trials
Cancer-related pain represents a major challenge in healthcare. A total of 40% of individuals with early- or intermediate-stage cancer and 90% of individuals with advanced cancer have moderateto-severe pain [1] . Pain in cancer patients may be caused by pre-existing pathologies, progression of the disease, tumor growth, bone metastases (cancer-induced bone pain) or the treatment of cancer itself [2] . Although not inevitable, pain requiring relief was prevalent in individuals with cancer, particularly in those with advanced disease [3] . The meta-analyses reported that pooled prevalence rates of pain were calculated according to four subgroups: • Studies that include patients after curative treatment (33%); www.expert-reviews.com
10.1586/ERA.10.236
• Studies including patients under anticancer treatment (59%); • Studies including patients characterized as advanced/metastatic/terminal disease (64%); • Studies including patients at all disease stages (53%). Of all the patients with pain, more than onethird graded their pain as moderate or severe [4] . Because cancer pain could destroy quality of life by making ordinary activities more difficult or even impossible to perform, pain management and palliative care should be the primary aim of treatment in late-stage cancer [5] . China is a developing country with the largest population in the world. Many medical facilities in China
© 2011 Expert Reviews Ltd
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are lagging behind and most patients are diagnosed at the terminal stage. There are more than 1 million patients each year suffering from cancer pain in China [6] . Rigorously designed and performed randomized controlled trials (RCTs) have the potential to generate the highest level of evidence for evaluating the efficacy of a given healthcare intervention [7] , but significant results are not recognized until a suitable measure of outcome is evaluated [8] . Research in China has been rapidly gaining momentum, but as yet there has been no systematic evaluation of the current standard of trials conducted in the treatment of cancer pain. Thus, standardization of cancer pain treatment in clinical trials was an imperative issue. While English-speaking countries have led this movement to standardization, there remained a limited amount of information from non-English-speaking countries, including China. The main purpose of this article is to provide an assessment of the quality of RCTs on the treatment of cancer pain conducted in China. To achieve this aim, all reports published from China from 1994 to 2009 have been examined to describe their general characteristics and evaluate the quality of their reporting.
Inclusion & exclusion criteria Types of studies
A RCT was defined as a prospective study assessing healthcare interventions with therapeutic intent in human participants who were randomly allocated to study groups [9] . We included any papers reporting RCTs on the treatment of cancer pain that took place in China and included Chinese citizens. Studies that did not state that they were randomized, did not deal with cancerrelated pain, or did not assess pain as an outcome measure, were excluded. Full journal publication was an inclusion criterion. A randomization sequence generated from a random number table, calculator or computerized random number generator was considered authentic. Types of participants
Participants with cancer-related pain (as defined by commonly used verbal rating scales or questionnaires), which was thought to be directly linked to the development of their cancer and caused by pre-existing pathologies or related to treatments; for example, chemotherapy-induced neuropathic pain [10] or procedures such as surgery.
Methods Search strategy
Types of interventions
The papers to be included in the analysis were searched in the PubMed database. Searches covered papers published from 1994 to 2009 and was performed on 29 September 2010. First, articles reporting RCTs were located by using ‘randomized controlled trial’ as a PubMed ‘publication type [pt]’ tag – this was also used as a denominator to gain relative frequency. Second, RCTs that referred to cancer pain were identified by using the free text terms ‘cancer’, ‘neoplasm’, ‘tumor’ or ‘carcinoma’. Third, RCTs published from China that referred to the treatment of cancer pain were searched using the following words: ‘randomized controlled trial’ [pt] AND (‘cancer’ [text] OR ‘neoplasm’ [text] OR ‘tumor’ [text] OR ‘carcinoma’ [text]) AND ‘pain’ [text] AND (China [address] OR Chinese [language]). Results were not only examined by abstracts of reporting, but were also assessed by hand in more detail from the text.
All therapeutic interventions that help relieve cancer pain compared with placebo, treatment as usual, an alternative presentation of interventions of the study group, no treatment, or other active interventions.
0.7 0.6 Trials (%)
0.5
Assessment of quality of reporting
The search included recommended items designed to report on the methodology and conduct of a study – those are common to many standard quality-assessment checklists. A subset of the Consolidated Standards of Reporting Trials (CONSORT) indicators was used or adapted in order to assess both the quality of reporting and, in those studies where information was provided, the actual conduct of the study [11] . Some customized indicators were also added in order to extract basic descriptive information that was specific to the Chinese papers (Table 1) . Overall quality scores or categories were not used to judge each paper because the use of summary scores could be problematic and often obscures individual aspects of quality [12] .
0.4
Data extraction & analysis
0.3 0.2 0.1 0 1994–1997
1998–2001
2002–2005
2006–2009
Time period (years)
Figure 1. Prevalence of reporting on the treatment of cancer pain in randomized controlled trials from 1994 to 2009.
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Each article was reviewed by two independent investigators (Liming Lu and Jingchun Zeng) who had received training in research methodology and statistics using an evaluation form (Table 1) . They extracted useful information. After completion, the results were compared to see whether they were consistent. Discrepancies were reviewed in detail and subsequently settled by consensus. Expert Rev. Anticancer Ther. 11(6), (2011)
Quality of reporting in randomized controlled trials on the treatment of cancer pain
Results
A total of 46 RCTs were included in full text ( Supplementary Table 7; see online at www. expertr eviews.com/doi/suppl/10.1586/ era.10.236).
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Table 1. Indicators used to describe and evaluate randomized controlled trials included in the analysis. Indicator
Description
Descriptive indicators Year of publication
As reported
Journal of publication
As reported
Publication language
Chinese or English
Nationality of authors
Chinese, international or collaboration
Funding source
As reported
Disease area
Simple categories
Choice of comparator interventions
Placebo/alternative treatment/no treatment
Evaluation of cancer pain intensity
VAS/NRS/VRS/others
A total of 46 papers were published in 27 journals. There were seven papers published in Chinese Journal of Intergrated Traditional and Western Medicine, six papers in Chinese Journal of Oncology, four papers in Chinese Journal of Cancer or Journal of Southern Medical University, two papers in National Medical Journal of China, Chinese Acupuncture and Moxibustion, or World Journal of Gastroenterology. Only one paper was published in Acta Radiologica, Digestive Diseases and Sciences, Oncology Reports, and so on.
Size of trial
Number of participants
Ethical committee approval
Yes/no
Informed consent from participants
As reported
Characteristics of the included trials Year distribution of publication
Counting the number of articles, frequency, which refers to the treatment of cancer pain in RCTs conducted in China, was found to increase over time: from one (2.2%) in 1994–1997 to 28 (60.9%) in 2006–2009 (Figure 1) . Journal of publication
Quality of reporting: CONSORT indicators Sample size
How was sample size determined?
Randomization
Was the trial randomized?
Allocation concealment
What method was used to implement the random allocation sequence?
Blinding
Whether or not patients and/or investigators were blinded to group assignment
Baseline characteristics
Were the baseline demographic and clinical characteristics of each group reported
Publication language
Primary outcomes
Of the 46 included RCT papers, 28 (60.9%) were written in Chinese. The remaining 18 papers (39.1%) were published in English.
Did they report which outcome was designated as the primary outcome?
Length of follow-up
As reported
Loss to follow-up
As reported
Statistical reporting
Were confidence intervals or p-values reported to indicate precision?
Nationality of authors
A total of 43 (93.5%) included papers were NRS: Numerical rating scale; VAS: Visual analogue scale; VRS: Verbal rating scale. written by authors in Chinese research institutes; the remaining papers were collaborations of Chinese Choice of comparator interventions and foreign researchers. There were no trials conducted or reported Table 3 shows the distributions of interventions in RCTs. The only by foreign researchers. largest number of interventions comprised of drugs (16 reports’ 34.8%) followed by Chinese medicine (15 reports; 32.6%); interFunding source ventional radiology and psychological intervention were studied Only seven articles (15.2%) reported their sources of funding. in fewer than 10% of all reports (Table 3) . Funding was obtained from provincial/municipal and national sources in five (10.9%) and two trials (4.3%), respectively. Evaluation of cancer pain intensity Funding from foreign pharmaceutical companies, universities, Visual analogue scale (VAS) was the main method of evaluation and international research agencies was not seen. of cancer pain (19 reports; 41.4%), while the numerical rating scale (NRS), verbal rating scale (VRS) and Bruggrman comDisease area fort score (BCS) were used less than VAS in evaluating cancer Cancer area of the RCTs focused on digestive system and multiple pain (Table 4) . systems (containing two systems or more) (Table 2) . Eight papers (17.4%) were studies in patients with pancreatic cancer, six papers Size of trials (13.0%) in bone metastases, and three papers (6.5%) in intestinal The number of participants in each included trial ranged from cancer or hepatic carcinoma. 18 to 400, with a median of 96 participants. www.expert-reviews.com
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Table 2. Body location of cancer in included trials.
Reporting of baseline characteristics
In total, 39 papers (84.8%) reported the details of the baseline characteristics of participants, in which 23 papers (50.0%) fully reported in table format. However, seven papers (15.2%) provided no information on the baseline characteristics or only stated that the baseline characteristics matched in both arms.
Cancer area
Papers (n)
Papers (%)
Digestive system
18
39.1
Motor system
8
17.4
Reproductive system
5
10.9
Respiratory system
3
6.5
Length of follow-up
Multiple systems
12
26.1
Total
46
100.0
In 22 papers (47.8%), there was no information provided on the length of time for which participants were followed. In total, 17 papers (37.0%) reported the date on which participants were recruited, 14 papers (30.4%) reported the follow-up duration, and only four papers (8.7%) reported the date on which follow-up ended. The length of follow-up (where stated) was from 1 month to more than 3 years.
Ethical issues (Ethics Committee Approval & Informed Consent)
Only 15 (32.6%) of the included trials reported approval by an ethics committee. Most of the study reports (29 reports, or 63.0%) did not provide any information regarding informed consent, although 17 papers (37.0%) stated that the participants did give consent. Quality of reporting Sample size
Only one (2.2%) of the papers mentioned sample size calculation.
Loss-to-follow-up
A total of 4.3% of the trials reported that no participants had dropped out (Table 6) . In total, 15.2% of all clinical trials showed a drop-out rate of 5% or less by the end of the study, and 17.4% of all the trials had a drop-out rate lower than 10%. A total of 36 studies (78.3%) failed to report drop-out rates.
Methods of randomization & allocation concealment
More than half of the included trials failed to report the details of their methods of randomization, and only referred to the word ‘randomization’ (Table 5) . In total, 12 studies (26.1%) were deemed to have authentic randomization: seven (15.2%) of the trials reported using a random number table to allocate participants; five (10.9%) used a computer allocation. Two (4.3%) used the date on which participants were invited to participate in, and two (4.3%) used the hospital record number. Allocation of participants according to their hospital record number or the date on which they were invited to participate in was not real randomization (these were quasi-randomizations; four trials, or 8.7%) [13] . Only four trials (8.7%) mentioned allocation concealment. Blinding
In total, 36 papers (78.3%) provided no information about blinding of either participants or investigators. In nine trials (19.6%), both the investigators and participants were blinded. In one trial (2.1%), only the participants were blind. Table 3. Type of intervention of included trials. Intervention
Papers (n)
Papers (%)
Drugs
16
34.8
Chinese medicine
15
32.6
Radiotherapy
4
8.7
Chemotherapy
4
8.7
Surgery
4
8.7
Interventional radiology
2
4.3
Psychological
1
2.2
Total
46
100.0
874
Statistical reporting
Only one paper (2.2%) did not report what statistical methods they had used. A total of 15 papers (32.6%) presented p-values, and no papers presented a 95% CI of the treatment effect. Statistical methods included T-tests, c2 tests, analysis of variance, and so on. Discussion
In cancer patients, pain is one of the most feared and burdensome symptoms. The high prevalence of cancer pain contrasts sharply with the rapidly increasing interest in pain and pain relief over the past decades [4] . The WHO introduced a pain ladder in 1986 that has been accepted worldwide [14] . Combined with appropriate dosage guidelines, it should be able to provide tools for adequate pain relief in 70–90% of patients [15] . However, pain in patients with advanced cancer is still not effectively controlled, and taking opioid analgesics long term may generate side effects such as nausea, vomiting, and even hallucinations and mental instability. China is a developing country with many patients suffering from cancer pain, so it is necessary to do more research in this field. Figure 1 shows the increasing trend in the number of RCTs conducted for the treatment of cancer pain in China. However, there are fewer papers in this field published in foreign journals, as funding sources and the chance of collaborative research with foreign researchers are still limited. Thus, it is necessary for Chinese research to keep up with international standards. In the trials reviewed, 32.6% reported approval by an ethics committee, while only 37.0% stated that the participants provided consent, which revealed that the reporting of ethical issues and informed consent may be inadequate in Chinese RCTs in this field. Although VAS, NRS and VRS are common methods that evaluate the intensity of cancer pain, we prefer to use VAS and/or NRS. VAS Expert Rev. Anticancer Ther. 11(6), (2011)
Quality of reporting in randomized controlled trials on the treatment of cancer pain
and NRS are used to judge the intensity of cancer pain directly by subjects themselves, while VRS is used to judge pain according to the recorded interviews given by subjects. Therefore, we think that the application of VAS or/and NRS are more objective and reasonable than VRS. In another study, 50.0% of included trials report details of baseline characteristics of participants in a table. However, significance tests of baseline differences are common in many of these trials. Tests of baseline differences are not necessarily wrong – they may be illogical [16] . Such hypothesis testing is superfluous and may mislead investigators and their readers. Rather, comparisons at baseline should be based on consideration of the prognostic strength of the variables measured and the size of any chance imbalances that have occurred [16] . In 46.8% of included trials, there was no information included regarding the length of time for which participants were followed. The date on which participants were recruited and follow-up ended, as well as follow-up duration, should be reported. Knowing when a study took place, and over what period participants were recruited, places the study in historical context. The length of follow-up is not always a fixed period after randomization. In many RCTs in which the outcome is time to an event, follow-up of all participants is ended on a specific date. This date should be provided, and it is also useful to report the minimum, maximum and median duration of follow-up [17] . However, 32.6% papers presented p-values and no papers presented a 95% CI. Almost all methods of analysis yielded an estimate of the treatment effect, which is in contrast to the outcomes shown in the comparison groups. Authors should accompany this with a confidence interval for the estimated effect, which indicates a central range of uncertainty for the true treatment effect [18] . Actual p-values (e.g., p = 0.003) are preferable to imprecise threshold reports such as p
